Inhibition of EZH2 primes the cardiac gene activation via removal of epigenetic repression during human direct cardiac reprogramming.
Inhibition of EZH2 primes the cardiac gene activation via removal of epigenetic repression during human direct cardiac reprogramming.
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EZH2 的抑制通过消除人类直接心脏重编程过程中的表观遗传抑制来启动心脏基因激活。
DOI：
10.1016/j.scr.2021.102365
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发表时间：
2021-05
影响因子：
1.2
通讯作者：
Zhou Y
中科院分区：
文献类型：
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作者：
Tang Y;Zhao L;Yu X;Zhang J;Qian L;Jin J;Lu R;Zhou Y
到目前为止，心血管疾病仍然是美国人死亡的主要原因。由于成年人心脏再生能力有限，心脏损伤造成的损害无法逆转，最终进展为心力衰竭。在心血管疾病治疗的需要中，已经提出了许多旨在细胞移植或细胞再生的疗法。将体细胞直接重编程为诱导心肌细胞（iCM）被认为是再生医学的一种有前途的策略。在小鼠模型中，可以通过体外和体内重编程因子的异位表达有效地实现从非肌细胞诱导心肌细胞，然而，人诱导的心肌细胞样细胞（hiCM）的产生仍然具有挑战性。hiCM生产的低效率要求在非肌细胞中鉴定可能抑制hiCM重编程的额外表观遗传记忆。在这里，我们进行了一个无偏见的功能丧失筛选，重点是表观遗传调节因子，并确定zeste同源物2（EZH2）的增强子作为一个重要的表观遗传障碍在hiCM重编程。我们发现，通过基因敲低或EZH2选择性降解剂的处理去除EZH2显著增加了hiCM重编程效率，并导致心脏基因的深度激活和胶原蛋白和细胞外基质基因的抑制。此外，靶向其催化活性的EZH2抑制剂也促进hiCM重编程，表明EZH2可能通过H3K27me3介导的基因抑制抑制心脏转换。事实上，H3K27me3的基因组分析揭示了心脏基因的一个子集，尽管递送了重编程因子，但其仍被高水平的H3K27me3抑制。然而，EZH2的抑制导致H3K27me3占用减少和这些心脏基因的强烈激活。综上所述，我们的数据表明EZH2抑制促进成纤维细胞中心脏基因的激活并减轻hiCM的产生。
Cardiovascular disease, until now, is still the leading cause of death in the United States. Due to the limited regenerative capacity of adult hearts, the damage caused by heart injury cannot be reversed and eventually progress into heart failure. In need of cardiovascular disease treatment, many therapies aimed at either cell transplantation or cell regeneration have been proposed. Direct reprogramming of somatic cells into induced cardiomyocytes (iCMs) is considered to be a promising strategy for regenerative medicine. The induction of cardiomyocytes from non-myocytes can be achieved efficiently via ectopic expression of reprogramming factors both in vitro and in vivo in the mouse model, however, the generation of human induced cardiomyocyte-like cells (hiCMs) remains challenging. The inefficiency of hiCMs production called for the identification of the additional epigenetic memories in non-myocytes which might be damping the hiCM reprogramming. Here, we conducted an unbiased loss-of-function screening focusing on epigenetic regulators and identified enhancer of zeste homolog 2 (EZH2) as an important epigenetic barrier during hiCM reprogramming. We found that the removal of EZH2 via genetic knockdown or treatment of EZH2 selective degrader significantly increased the hiCM reprogramming efficiency and led to profound activation of cardiac genes and repression of collagen and extracellular matrix genes. Furthermore, EZH2 inhibitors targeting its catalytic activity also promotes hiCM reprogramming, suggesting that EZH2 may restrain cardiac conversion through H3K27me3-mediated gene repression. Indeed, genomic profiling of H3K27me3 revealed a subset of cardiac genes that remain repressed with high levels of H3K27me3 despite of the delivery of the reprogramming factors. Inhibition of EZH2, however, leads to reduced H3K27me3 occupancy and robust activation of these cardiac genes. Taken together, our data suggested that EZH2 inhibition facilitates the activation of cardiac genes in fibroblasts and eases the production of hiCMs.
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影响因子：
16.6
作者：
Gilsbach R;Schwaderer M;Preissl S;Grüning BA;Kranzhöfer D;Schneider P;Nührenberg TG;Mulero-Navarro S;Weichenhan D;Braun C;Dreßen M;Jacobs AR;Lahm H;Doenst T;Backofen R;Krane M;Gelb BD;Hein L
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影响因子：
8
作者：
Gonzalez, M. E.;Li, X.;Toy, K.;DuPrie, M.;Ventura, A. C.;Banerjee, M.;Ljungman, M.;Merajver, S. D.;Kleer, C. G.
通讯作者：
Kleer, C. G.
影响因子：
1.2
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作者：
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82.9
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